CN105693727B - 8-（Tertbutyloxycarbonyl）The synthetic method of -6,7,8,9- tetrahydrochysenes -5- hydrogen-imidazoles [1,5-a] [1,4] diaza -6- carboxylic acids - Google Patents
8-（Tertbutyloxycarbonyl）The synthetic method of -6,7,8,9- tetrahydrochysenes -5- hydrogen-imidazoles [1,5-a] [1,4] diaza -6- carboxylic acids Download PDFInfo
- Publication number
- CN105693727B CN105693727B CN201410695249.9A CN201410695249A CN105693727B CN 105693727 B CN105693727 B CN 105693727B CN 201410695249 A CN201410695249 A CN 201410695249A CN 105693727 B CN105693727 B CN 105693727B
- Authority
- CN
- China
- Prior art keywords
- imidazoles
- hydrogen
- tetrahydrochysenes
- diaza
- tertbutyloxycarbonyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The present invention relates to one kind 8（Tertbutyloxycarbonyl）The synthetic method of 6,7,8,9 tetrahydrochysene, 5 hydrogen imidazoles [1,5 a] [1,4] diaza, 6 carboxylic acid.The present invention is raw material using 1 hydrogen imidazoles, 4,5 dioctyl phthalate that is easy to get, and 8 have been synthesized by ten steps（Tertbutyloxycarbonyl）6,7,8,9 tetrahydrochysene, 5 hydrogen imidazoles [1,5 a] [1,4] diaza, 6 carboxylic acid.8‑（Tertbutyloxycarbonyl）6,7,8,9 tetrahydrochysene, 5 hydrogen imidazoles [1,5 a] [1,4] diaza, 6 carboxylic acid is a kind of useful organic synthesis intermediate.
Description
Technical field
The present invention relates to 8-（Tertbutyloxycarbonyl）- 6,7,8,9- tetrahydrochysenes -5- hydrogen-imidazoles [1,5-a] [1,4] diaza -6-
The practicability synthetic method of carboxylic acid.
Background technology
8-（Tertbutyloxycarbonyl）- 6,7,8,9- tetrahydrochysenes -5- hydrogen-imidazoles [1,5-a] [1,4] diaza -6- carboxylic acids（No. CAS：
1251003-93-6）It is a kind of useful organic synthesis intermediate.It is less to the Industrialized synthesis method report of the intermediate.And
There is its important role in organic synthesis and pharmaceutical synthesis by each analog derivative of parent nucleus of the compound.
Invention content
The purpose of the present invention is develop a kind of new 8-（Tertbutyloxycarbonyl）- 6,7,8,9- tetrahydrochysenes -5- hydrogen-imidazoles [1,5-
A] [1,4] diaza -6- carboxylic acids synthetic method.Mainly solve that there is presently no suitable industry to be combined to 8-（Tertiary butyloxycarbonyl
Base）The technical issues of method of -6,7,8,9- tetrahydrochysenes -5- hydrogen-imidazoles [1,5-a] [1,4] diaza -6- carboxylic acids.
Technical scheme of the present invention：A kind of 8-（Tertbutyloxycarbonyl）- 6,7,8,9- tetrahydrochysenes -5- hydrogen-imidazoles [1,5-a] [1,
4] synthetic method of diaza -6- carboxylic acids, includes the following steps：It is synthesized using 10 footworks, the first step is with regular industrial raw material 1-
Hydrogen imidazoles -4,5- dioctyl phthalate flows back in acetic anhydride for starting material and obtains 1- hydrogen imidazoles -5- formic acid；Second step, 1- hydrogen imidazoles-
5- formic acid flows back in methanol hydrochloride solution obtains 1- hydrogen imidazoles -5- methyl formates；Three-step reaction in the presence of triethyl amine,
1- is obtained by the reaction under 0 degree Celsius with 2- bromomethyls-ethyl acrylate（2-（Carbethoxyl group）Allyl）- 5- methyl formates-miaow
Azoles；1- is obtained by the reaction with benzylamine under the effect of 1,8- diazabicylo hendecane -7- alkene in 4th step（2-（Benzylamine ylmethyl）-3-
Ethyl propionate base）- 5- Ethyl formates-imidazoles；9- carbonyl -6,7,8,9- tetrahydrochysenes-[1,5- is obtained by the reaction in the catalysis of 5th step palladium carbon
A] [1,4] diaza -6- carboxylate methyl esters；6th step protects 9- carbonyl -6,7,8,9- tetrahydrochysene-[1,5-a] with dimethyl dicarbonate butyl ester
[1,4] amido bond of diaza -6- carboxylate methyl esters；For 7th step compound 7 under lithium triethylborohydride effect, 0 to -78 is Celsius
It is reacted under the conditions of degree, -78 degrees Celsius obtain optimal yield；8th step synthesizes 6- under the action of triethylsilane and trifluoroacetic acid
- 5 hydrogen of methyl -6,7,8,9- tetrahydrochysenes-imidazoles [1,5-a] [1,4] diaza -6- carboxylates；9th step is protected with dimethyl dicarbonate butyl ester
Shield amino obtains 8- tertiary butyl -6- methyl -6,7- dihydros -5- hydrogen-imidazoles [1,5-a] [1,4] diaza -6,8（9 hydrogen）- two carbonyls
Base ester；Tenth step obtains final products 8- with lithium hydrate ester group（Tertbutyloxycarbonyl）- 6,7,8,9- tetrahydrochysenes -5- hydrogen-miaow
The synthesis of azoles [1,5-a] [1,4] diaza -6- carboxylic acids.Reaction equation is as follows：
In above-mentioned technique, first step reaction temperature is 80 DEG C, higher with thionyl chloride esterification yield than conventional, is more easy to realize
Industrialization；Second step reaction temperature is controlled at 70 DEG C；Four-step reaction solvent is dichloromethane, and reaction temperature is room temperature；5th
Temperature control is walked at 20-50 DEG C, the weight percent containing palladium of palladium carbon is 10%；8th step reaction temperature is 60 DEG C；Tenth step is reacted
The solvent used is methanol, and reaction temperature is 25 DEG C.
Beneficial effects of the present invention：Reaction process reasonable design of the present invention, stable reaction conditions are easily-controllable, and purifying is convenient.Its
Raw material -1- hydrogen imidazoles -4, the 5- dioctyl phthalate for using energy large-scale production cheap and easy to get, 8- has been synthesized by ten steps（Tertiary fourth
Oxygen carbonyl）- 6,7,8,9- tetrahydrochysenes -5- hydrogen-imidazoles [1,5-a] [1,4] diaza -6- carboxylic acids.
Specific implementation mode
The synthesis of hydrogen imidazoles 5- formic acid
900 grams of 1- hydrogen imidazoles -4,5- dioctyl phthalate are added in glacial acetic acid solvent, are flowed back 40 hours.Reaction finishes,
Solvent is spin-dried for, obtained crude product is washed with ethyl alcohol, and 1- hydrogen imidazoles -5- formic acid, yield is obtained by filtration：63 %.
HNMR (DMSO): δ7.71 (s,1H), 7.60(s,1H)。
The synthesis of hydrogen imidazoles -5- methyl formates
Embodiment 1
30 g of compound 2 are added in methanol solution, thionyl chloride is added dropwise in cryogenic conditions, then reacts at room temperature 12h.
It is spin-dried for solvent, crude product is dissolved in dichloromethane, aqueous ammonium chloride solution washing, silica gel column purification, yield：70%.
HNMR (MeOD):δ 7.77 (d, 2H), 3.85 (s, 3 H).
Embodiment 2
300 g of compound 2 are added in methanol hydrochloride solution, are flowed back 20 hours.TLC (dichloromethane：Methanol
Volume ratio=10：1, Rf=0.4) display reaction terminates.It is spin-dried for solvent, the methanol solution of crude product triethylamine is neutralized to pH=9,
It is spin-dried for solvent again, crude product is dissolved in dichloromethane, and the next step is directly used in without purifying.Yield about 100%.
HNMR (MeOD):δ 7.77 (d, 2H), 3.85 (s, 3 H).
（2-（Carbethoxyl group）Allyl）The synthesis of -5- methyl formates-imidazoles
600 g of compound 3 and triethylamine are added in dichloromethane, 2- bromines are slowly added dropwise to reaction system at 0 DEG C
Methyl-acrylic acid ethyl ester.It is added dropwise, TLC (dichloromethane：Methanol volume ratio=20：1, Rf=0.5) display reaction knot
Beam, crude product directly obtain product 4, yield with column chromatography：8.7%.
（2-（Benzylamine ylmethyl）- 3 ethyl propionate bases）The synthesis of -5- Ethyl formates-imidazoles
111 g of compound 4 are dissolved in dichloromethane solution, 61.5 g of compound 1.8- diazas two are added at room temperature
Ring hendecane -7- alkene, is then added dropwise benzylamine.It is added dropwise, is stirred at room temperature 20 hours.TLC (petroleum ethers：Ethyl acetate volume ratio
= 1：1, Rf=0.5) display reaction terminates.Crude product is purified to obtain compound 5, yield with column chromatography：71.8%.
The synthesis of carbonyl -6,7,8,9- tetrahydrochysenes-[1,5-a] [1,4] diaza -6- carboxylate methyl esters
Embodiment 1
100 g of compound 5 and 40 grams of palladium carbons are dissolved in methanol solution, system is at 20 DEG C, the Hydrogen Vapor Pressure condition of 50 pas
Lower reaction 6 hours.TLC (petroleum ethers：Ethyl acetate volume ratio=2：1, Rf=0.6) display reaction terminates.Solution uses diatom
Soil filtering, filtrate is spin-dried for obtaining crude product, which is washed with ethyl acetate, filtering, dry compound 6, yield：21.1%.
HNMR (CDCl3): δ7.90 (s, 1H), 7.65 (s, 1H), 4.21 (m, 2H), 4.05-3.96 (m, 2H),
3.44-3.25 (m, 2H), 315-3.00 (m, 1H), 1.29 (3H)。
Embodiment 2
10 g of compound 5 and 4 grams of palladium carbons are dissolved in ethanol solution, system is under the conditions of 35 DEG C, the Hydrogen Vapor Pressure of 50 pas
Reaction 6 hours.TLC (petroleum ethers：Ethyl acetate volume ratio=2：1, Rf=0.6) display reaction terminates.Solution diatomite
Filtering, filtrate is spin-dried for obtaining crude product, which is washed with ethyl acetate, filtering, dry compound 6, yield：75.1%.HNMR
(CDCl3): δ7.90 (s, 1H), 7.65 (s, 1H), 4.21 (m, 2H), 4.05-3.96 (m, 2H), 3.44-
3.25 (m, 2H), 315-3.00 (m, 1H), 1.29 (3H)。
Embodiment 3
100 g of compound 5 and 40 grams of palladium carbons are dissolved in ethanol solution, system is at 50 DEG C, the Hydrogen Vapor Pressure condition of 50 pas
Lower reaction 6 hours.TLC (petroleum ethers：Ethyl acetate volume ratio=2：1, Rf=0.6) display reaction terminates.Solution uses diatom
Soil filtering, filtrate is spin-dried for obtaining crude product, which is washed with ethyl acetate, filtering, dry g of compound 6, yield：82%.
HNMR (CDCl3): δ7.90 (s, 1H), 7.65 (s, 1H), 4.21 (m, 2H), 4.05-3.96 (m, 2H),
3.44-3.25 (m, 2H), 315-3.00 (m, 1H), 1.29 (3H)。
Tertiary butyl -6- methyl -9- oxygen -6,7- dihydros -5- hydrogen-imidazoles [1,5-a] [1,4] diaza -6,8（9 hydrogen）Dicarboxyl
The synthesis of acid esters
29 g of compound 6 and 8.5 grams of dimethyl aminopyridines are dissolved in dichloromethane solution, are slowly added at room temperature
Dimethyl dicarbonate butyl ester, charging finish reaction and are stirred overnight at room temperature.Reaction is quenched with 0.5 mole every liter of dilute hydrochloric acid solution, is detached
Organic phase, organic phase are dried with anhydrous sodium sulfate, are spin-dried for obtaining 40 g of compound 7, yield：93.4%.
HNMR (CDCl3): δ7.50 (s, 1H), 7.35 (s, 1H), 8.23(s, 1H), 4.83 - 4.60
(m, 2H), 4.24 (q, J=7.1 Hz, 2H), 3.67 (td, J=5.3, 14.9 Hz, 1H), 3.46 (td, J=
5.6, 14.9 Hz, 1H), 3.37 - 3.25 (m, 1H), 1.39 - 1.20 (m, J=7.1, 7.1 Hz, 3H)。
Tertiary butyl -6- methyl -9- hydroxyl -6,7- dihydros -5- hydrogen-imidazoles [1,5-a] [1,4] diaza -6,8（9 hydrogen）- two
The synthesis of carboxylate
Embodiment 1
4 g of compound 7 are dissolved in dry tetrahydrofuran solution, boron triethyl is slowly added dropwise into reaction solution at 0 DEG C
Lithium hydride solution.It is added dropwise, reaction is stirred 12 hours at 25 DEG C.Reaction finishes, and the dilute hydrochloric acid with 0.5 mole every liter is molten
Liquid adjusts pH to 9, isolates organic phase, is dried with anhydrous sodium sulfate, silica gel post separation is concentrated to give 1 g compounds 8, yield
25%。
Embodiment 2
4 g of compound 7 are dissolved in dry tetrahydrofuran solution, triethyl group is slowly added dropwise into reaction solution at -30 DEG C
Lithium borohydride solution.It is added dropwise, reaction is stirred 6 hours at 0 DEG C.TLC (petroleum ethers：Ethyl acetate volume ratio=2：1,
Rf=0.4) display reaction terminates.PH to 9 is adjusted with 0.5 mole every liter of dilute hydrochloric acid solution, isolates organic phase, use is anhydrous
Sodium sulphate is dried, and silica gel post separation is concentrated to give 1.8 g compounds 8, yield 45%.
Embodiment 3
40 g of compound 7 are dissolved in dry tetrahydrofuran solution, three second are slowly added dropwise at -78 DEG C into reaction solution
Base lithium borohydride solution.It is added dropwise, reaction is stirred 4 hours at -78 DEG C.TLC (petroleum ethers：Ethyl acetate volume ratio=2：
1, Rf=0.4) display reaction terminates.PH to 9 is adjusted with 0.5 mole every liter of dilute hydrochloric acid solution, isolates organic phase, is used
Anhydrous sodium sulfate is dried, and silica gel post separation is concentrated to give 3.5 g compounds 8, yield 87.5%.
The synthesis of methyl -6,7,8,9- tetrahydrochysenes -5- hydrogen-imidazoles [1,5-a] [1,4] diaza -6- carboxylates
40 g of compound, 8,200 milliliters of triethylsilanes and 200 milliliters of trifluoroacetic acids are dissolved in dichloromethane solution, instead
System is answered to flow back 4 hours.TLC (dichloromethane：Methanol volume ratio=10：1, Rf=0.5) display reaction terminates.Reaction solution
It is neutralized, organic phase separation, is spin-dried for after anhydrous sodium sulfate drying, crude product is directly used in the next step with saturated sodium carbonate solution.
Tertiary butyl -6- methyl 6,7- dihydros -5- hydrogen-imidazoles [1,5-a] [1,4] diaza -6,8（9 hydrogen）Dicarbapentaborane ester
Synthesis
40 g of compound 9 are dissolved in tetrahydrofuran solution, dimethyl dicarbonate butyl ester is slowly added to reaction system, are fed
After, it is stirred at room temperature 1 hour.TLC (dichloromethane：Methanol volume ratio=10：1, Rf=0.5) display reaction terminates thick
Product obtain compound 10, yield with column chromatography：96%.
1H NMR (MeOD): δ= 7.59 (br. s., 1H), 6.82 (br. s., 1H), 4.68 - 4.49
(m, 2H), 4.46 - 4.28 (m, 2H), 4.13 (m, 1H), 3.88 - 3.63 (m, 1H), 3.68 (s, 3H)
2.84 (br. s., 1H), 1.40 (br. s., 9H) 。
（Tertbutyloxycarbonyl）The synthesis of -6,7,8,9- -5 hydrogen of tetrahydrochysene-imidazoles [1,5-a] [Isosorbide-5-Nitrae] diaza -6- carboxylic acids
40 g of compound 10 are dissolved in methanol solution, it is 20% lithium hydroxide that mass percentage concentration, which is added, to reaction system
Aqueous solution.It is stirred at room temperature 3 hours, system 0.5 mole every liter of dilute hydrochloric acid solution adjusting pH to 6-7, reaction after completion of the reaction
Liquid is extracted with dichloromethane, and extract liquor is dried with anhydrous sodium sulfate, is spin-dried for obtaining compound 11, yield：80%.
1H NMR (MeOD): δ= 7.52 (br. s., 1H), 6.81 (br. s., 1H), 4.58 - 4.19
(m, 2H), 4.01 – 3.97 (m, 2H), 3.57 (m, 1H), 3.42 - 3.22 (m, 1H), 2.04 (br.
s., 1H), 1.40 (br. s., 9H) 。
Claims (7)
1. a kind of 8-（Tertbutyloxycarbonyl）The conjunction of -6,7,8,9- tetrahydrochysenes -5- hydrogen-imidazoles [1,5-a] [1,4] diaza -6- carboxylic acids
At method, include the following steps：It is synthesized using 10 footworks, the first step is with regular industrial raw material 1- hydrogen imidazoles -4,5- dioctyl phthalate
Starting material flows back in acetic anhydride obtains 1- hydrogen imidazoles -5- formic acid；Second step, 1- hydrogen imidazoles -5- formic acid are molten in hydrochloric acid methanol
Reflux obtains 1- hydrogen imidazoles -5- methyl formates in liquid；Three-step reaction in the presence of triethyl amine, with 2- bromomethyls-acrylic acid
1- is obtained by the reaction under 0 degree Celsius in ethyl ester（2-（Carbethoxyl group）Allyl）- 5- methyl formates-imidazoles；4th step is in 1,8- bis-
Under the effect of azabicyclic hendecane -7- alkene, 1- is obtained by the reaction with benzylamine（2-（Benzylamine ylmethyl）Ethyl 3--propanoate base）- 5- first
Acetoacetic ester-imidazoles；9- carbonyl -6,7,8,9- tetrahydrochysenes-[1,5-a] [1,4] diaza -6- is obtained by the reaction in the catalysis of 5th step palladium carbon
Carboxylate methyl ester；6th step protects 9- carbonyl -6,7,8,9- tetrahydrochysenes-[1,5-a] [1,4] diaza -6- carboxylics with dimethyl dicarbonate butyl ester
The amido bond of sour methyl esters；7th step compound 7 is reacted under lithium triethylborohydride effect under 0 to -78 degrees celsius；The
Eight steps synthesized under the action of triethylsilane and trifluoroacetic acid -5 hydrogen of 6- methyl -6,7,8,9- tetrahydrochysenes-imidazoles [1,5-a] [1,
4] diaza -6- carboxylates；9th step protects amino to obtain 8- tertiary butyl -6- methyl -6,7- dihydros -5- with dimethyl dicarbonate butyl ester
Hydrogen-imidazoles [1,5-a] [1,4] diaza -6,8（9 hydrogen）Dicarbapentaborane ester；Tenth step is obtained finally with lithium hydrate ester group
Product 8-（Tertbutyloxycarbonyl）- 6,7,8,9- tetrahydrochysenes -5- hydrogen-imidazoles [1,5-a] [1,4] diaza -6- carboxylic acids；Reaction equation is as follows
。
2. a kind of 8- according to claim 1（Tertbutyloxycarbonyl）- 6,7,8,9- tetrahydrochysenes -5- hydrogen-imidazoles [1,5-a] [1,
4] synthetic method of diaza -6- carboxylic acids, it is characterized in that：80 DEG C of first step reaction temperature.
3. 8- according to claim 1（Tertbutyloxycarbonyl）- 6,7,8,9- tetrahydrochysenes -5- hydrogen-imidazoles [1,5-a] [1,4] two
The synthetic method of azepine -6- carboxylic acids, it is characterized in that：70 DEG C of second step reaction temperature.
4. 8- according to claim 1（Tertbutyloxycarbonyl）- 6,7,8,9- tetrahydrochysenes -5- hydrogen-imidazoles [1,5-a] [1,4] two
The synthetic method of azepine -6- carboxylic acids, it is characterized in that：Four-step reaction solvent is dichloromethane, and reaction temperature is room temperature.
5. 8- according to claim 1（Tertbutyloxycarbonyl）- 6,7,8,9- tetrahydrochysenes -5- hydrogen-imidazoles [1,5-a] [1,4] two
The synthetic method of azepine -6- carboxylic acids, it is characterized in that：5th step temperature is controlled in 20-50oThe weight percent containing palladium of C, palladium carbon is
10%。
6. 8- according to claim 1（Tertbutyloxycarbonyl）- 6,7,8,9- tetrahydrochysenes -5- hydrogen-imidazoles [1,5-a] [1,4] two
The synthetic method of azepine -6- carboxylic acids, it is characterized in that：8th step reaction temperature is 60 DEG C.
7. 8- according to claim 1（Tertbutyloxycarbonyl）- 6,7,8,9- tetrahydrochysenes -5- hydrogen-imidazoles [1,5-a] [1,4] two
The synthetic method of azepine -6- carboxylic acids, it is characterized in that：The solvent that the reaction of tenth step is used is methanol, and reaction temperature is 25 DEG C.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410695249.9A CN105693727B (en) | 2014-11-27 | 2014-11-27 | 8-（Tertbutyloxycarbonyl）The synthetic method of -6,7,8,9- tetrahydrochysenes -5- hydrogen-imidazoles [1,5-a] [1,4] diaza -6- carboxylic acids |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410695249.9A CN105693727B (en) | 2014-11-27 | 2014-11-27 | 8-（Tertbutyloxycarbonyl）The synthetic method of -6,7,8,9- tetrahydrochysenes -5- hydrogen-imidazoles [1,5-a] [1,4] diaza -6- carboxylic acids |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105693727A CN105693727A (en) | 2016-06-22 |
| CN105693727B true CN105693727B (en) | 2018-10-16 |
Family
ID=56294886
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410695249.9A Active CN105693727B (en) | 2014-11-27 | 2014-11-27 | 8-（Tertbutyloxycarbonyl）The synthetic method of -6,7,8,9- tetrahydrochysenes -5- hydrogen-imidazoles [1,5-a] [1,4] diaza -6- carboxylic acids |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105693727B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107325101B (en) * | 2017-06-29 | 2019-03-26 | 上海合全药物研发有限公司 | The synthetic method of 6- methylol -6,7- dihydro -5H, 9H- imidazo diazepine -8- carboxylic acid tert-butyl ester |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101146540A (en) * | 2004-06-09 | 2008-03-19 | 默克公司 | HIV integrase inhibitors |
| WO2012083224A1 (en) * | 2010-12-17 | 2012-06-21 | Vanderbilt University | Bicyclic triazole and pyrazole lactams as allosteric modulators of mglur5 receptors |
| CN102958935A (en) * | 2010-04-02 | 2013-03-06 | 爱尔兰詹森研发公司 | Macrocyclic integrase inhibitors |
| WO2014149164A1 (en) * | 2013-03-15 | 2014-09-25 | Celgene Avilomics Research, Inc. | Mk2 inhibitors and uses thereof |
-
2014
- 2014-11-27 CN CN201410695249.9A patent/CN105693727B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101146540A (en) * | 2004-06-09 | 2008-03-19 | 默克公司 | HIV integrase inhibitors |
| CN102958935A (en) * | 2010-04-02 | 2013-03-06 | 爱尔兰詹森研发公司 | Macrocyclic integrase inhibitors |
| WO2012083224A1 (en) * | 2010-12-17 | 2012-06-21 | Vanderbilt University | Bicyclic triazole and pyrazole lactams as allosteric modulators of mglur5 receptors |
| WO2014149164A1 (en) * | 2013-03-15 | 2014-09-25 | Celgene Avilomics Research, Inc. | Mk2 inhibitors and uses thereof |
Non-Patent Citations (1)
| Title |
|---|
| Non-peptide glycoprotein IIb/IIIa inhibitors. 6.Design and synthesis of rigid, centrally constrained non-peptide fibrinogen receptor antagonists;Askew, B. C.等;《Bioorganic & Medicinal Chemistry Letters》;19951231;第5卷(第5期);第475-480页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105693727A (en) | 2016-06-22 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108129288B (en) | Synthesis method of trans-3-hydroxycyclobutylformic acid | |
| CN102816200B (en) | Method for preparing abiraterone acetate | |
| ES2548078T3 (en) | Asymmetric synthesis method, related starting material and method of preparation of (S, S) -2,8-diazabicyclo [4,3,0] nonane | |
| CN107501112B (en) | A kind of Chiral Synthesis of chiral beta-amino acids and the synthetic method of medicine intermediate | |
| CN107011404B (en) | A method of using cholic acid as Material synthesis lithocholic acid | |
| CN105693727B (en) | 8-（Tertbutyloxycarbonyl）The synthetic method of -6,7,8,9- tetrahydrochysenes -5- hydrogen-imidazoles [1,5-a] [1,4] diaza -6- carboxylic acids | |
| CN106892928B (en) | A kind of synthetic method of tertiary butyl -8- hydroxyls -5- oxa- -2- azaspiros [3.5] nonane -2- carboxylates | |
| CN105418620B (en) | A kind of synthetic method of 4- (tertbutyloxycarbonyl) octahydros furans simultaneously [3,2-b] pyridine -6- carboxylic acids | |
| CN107216332B (en) | The synthetic method of 5 (6H) formic acid base ester of tert-butyl -7- methylol -7,8- dihydro 4H pyrazolo diazepine | |
| CN101979376A (en) | Method for preparing glycinamide hydrochloride | |
| CN108239019B (en) | Synthesis method of (2S,5S or 5R) -N-tert-butyloxycarbonyl-5-hydroxy-2-ethyl piperidinecarboxylate | |
| CN106588921B (en) | A kind of synthetic method of the methyl formate of 7 azaindole 3 | |
| CN103073480B (en) | A kind of preparation method of the carboxylic acid of 2 penta [c] pyrroles of (tertbutyloxycarbonyl) octahydro ring 5 | |
| CN102786543A (en) | Preparation methods for imidazole[1,2-a]pyridine-6-boric acid pinacol ester and derivatives thereof | |
| CN108947908B (en) | New intermediate of brivaracetam with imidazole ring and synthesis method and application thereof | |
| CN105440041A (en) | Synthetic method of 7-tert-butyl-2-ethyl-8-methyl-5,6-glyoxalidine[1,2-a] pyrazine-2,7(8H)-dicarboxylic acid | |
| CN101514201A (en) | Preparation method for (4,7-cis)-octahydro-pyrrolo[3,4-b]pyridine and moxifolxacin | |
| CN101723879B (en) | Method for synthesizing (R)-3-ethyl piperidine hydrochloride | |
| CN108101852A (en) | A kind of preparation method of olaparib | |
| CN107312011A (en) | The synthetic method of the carboxylic acid of 2,7 diaza spiro nonane of racemic 7 tert-butoxycarbonyl, 1 oxygen subunit 4 | |
| CN107235982B (en) | The synthetic method of 5 (6H) carboxylate of tert-butyl 7- hydroxyl -7,8- dihydro -4H- pyrazolo diazepine | |
| CN105111136B (en) | A kind of method for preparing the ketone of 3 methyl, 1 piperidine 4 or the ketone of 1 piperidine 4 | |
| CN107383033A (en) | The synthetic method of cis 5 tertbutyloxycarbonyl tetrahydrofuran simultaneously [3,4 c] pyrroles's 3A carboxylate methyl esters | |
| CN107383034A (en) | The synthetic method of (tertbutyloxycarbonyl) octahydro of racemic 5 furans simultaneously [3,2 c] pyridine 3a carboxylic acids | |
| CN110551129B (en) | Preparation method of 4, 5-dihydro-1H, 3H-pyrrolo [1,2-A ] [1,4] diazepine-2, 4-dicarboxylic acid-2-tert-butyl ester |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20170331 Address after: Jinshan District of Shanghai chemical industrial zone of Shanghai city Jinshan District 201507 (West) Yuegong Road No. 9 Applicant after: Shanghai SynTheAll Pharmaceutical Co., Ltd. Applicant after: Shanghai STA Pharmaceutical R & D Co., Ltd. Applicant after: CHANGZHOU HEQUAN PHARMACEUTICAL CO., LTD. Applicant after: Changzhou whole new drug research and Development Co., Ltd. Address before: Jinshan District of Shanghai chemical industrial zone of Shanghai city Jinshan District 201507 (West) Yuegong Road No. 9 Applicant before: Shanghai SynTheAll Pharmaceutical Co., Ltd. Applicant before: Shanghai STA Pharmaceutical R & D Co., Ltd. Applicant before: CHANGZHOU HEQUAN PHARMACEUTICAL CO., LTD. |
|
| TA01 | Transfer of patent application right | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20190104 Address after: 201507 No. 9 Yuegong Road, Jinshan District, Shanghai Chemical Industry Zone, Jinshan District, Shanghai Co-patentee after: Shanghai STA Pharmaceutical R & D Co., Ltd. Patentee after: Shanghai SynTheAll Pharmaceutical Co., Ltd. Co-patentee after: CHANGZHOU HEQUAN PHARMACEUTICAL CO., LTD. Address before: 201507 No. 9 Yuegong Road, Jinshan District, Shanghai Chemical Industry Zone, Jinshan District, Shanghai Co-patentee before: Shanghai STA Pharmaceutical R & D Co., Ltd. Patentee before: Shanghai SynTheAll Pharmaceutical Co., Ltd. Co-patentee before: CHANGZHOU HEQUAN PHARMACEUTICAL CO., LTD. Co-patentee before: Changzhou whole new drug research and Development Co., Ltd. |
|
| TR01 | Transfer of patent right |